Hereditary hemochromatosis (HH) is the most common inherited disorder among Caucasians with an estimated frequency as high as 8 per 1000. Affected individuals absorb excessive amounts of dietary iron and develop progressive accumulation of tissue iron stores with consequent organ dysfunction including hepatic cirrhosis, diabetes mellitus, congestive heart failure, arthropathy and impotence. Early diagnosis and institution of phlebotomy treatments will prevent disease manifestations and normalize life expectancy. HH is therefore a natural target for the development of a routine screening strategy. Our group has demonstrated the favorable cost-effectiveness ratio of adopting such a screening strategy (1) and has screened 16,031 primary care patients using serum transferrin saturation (TS) levels to confirm the prevalence of undiagnosed HH in this setting and to demonstrate the feasibility of screening. (2) The recent description of HFE gene mutations in individuals with HH has made genetic testing for HH possible and may increase the attractiveness of general screening. However, several important questions about genetic prevalence and penetrance remain to be addressed before such a recommendation can be made. Our large screened sample provides us a unique opportunity to address several of these important issues. First, we will obtain population-based estimates of the prevalence of HFE gene mutations. Second, we will determine the sensitivity of serum TS testing for detecting these mutations. Third, the comparison of genotype and phenotype will allow us to draw useful inferences about disease penetrance. The results will enable us to propose an optimal screening strategy for HH and to determine the place of genetic testing in the diagnostic algorithm. This strategy may vary depending on age, sex and race. The answers to these questions will enable us to determine with greater confidence the relative effectiveness of a screening strategy for HH and will clarify for primary care practitioners which of their patients should be screened for this disorder. These questions have recently been identified as a priority by the Centers for Disease Control and Prevention and by the National Heart Lung and Blood Insitute.